SU1544187A3 - Method of producing derivatives of 1,5-benzthiazepine or their salts - Google Patents

Abstract

The invention relates to heterocyclic compounds, in particular (+) - cis-2- (4-methoxyphenyl) -3-hydroxy-5- [2- (N, N-dimethylamino) ethyl] -8-chloro-2,3-dihydro- 1,5-Benzothiazepin-4 (5H) -one, (+) - cis-2- (4-methoxyphenyl) -3-acetoxy-5- [2- (N, N-dimethylamino) ethyl] -8-chloro 2,3-dihydro-1,5-benzothiazepin-4 (5H) -one and (±) -cis-2- (4-methoxyphenyl) -3-acetoxy-5- [2- (dimethylamino) ethyl] -8- chloro-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one hydrochloride, which exhibit hypotensive, cerebral and coronary vasodilator activity and can be used in medicine. The goal is to create new, more active compounds of the specified class. Synthesis is carried out by the alkylation reaction of the corresponding amino derivative 1,5-benzothiazepine with an alkylating agent — an alkanol, alkyl sulfonate, diazoalkane, quaternary alkyl ammonium, alkyl halide, alkyl sulfonate (in all cases, lower alkyl). Mp, ° C

gross-la

% yield: a) 121-123 ° С

C ₂₀ CLH ₂₁ N ₂ O ₃

90: b) 158-160 ° С

C ₂₂ CLH ₂₃ N ₂ O ₄

88: c) 128-132 ° C

C ₂₀ CLH ₂₂ N ₂ O ₃

90. New compounds exhibit high antihypertensive activity, exceeding diltiazem by 3.2-11 times, with LD toxicity of ₅₀ * 981000 mg / kg. 4 hp f-ly. 6 tab.

Description

The invention relates to a method for the preparation of new 1,5-benzothiazepine derivatives or their salts, which exhibit hypotensive, cerebral and coronary vasodilator activity and can be used in medicine.

The purpose of the invention is the creation of new derivatives of 1,5-benzothiazepine, showing improved hypotensive, cerebral and coronary vasodilating properties in this series of compounds.

Example 1. 690 mg of (+) - cis-2- - (4-hydroxyphenyl) -3-hydroxy-5- 2- (N, N-dimethylamino) ethyl-8-chloro-2,3-dihydro- -1, 5-benzothiazepin-4 (5H) -one is dissolved in 20 ml of tetrahydrofuran. 78 mg of sodium hydride (60% oily form) are added to the solution at room temperature and stirred for 30 minutes at the same temperature. Then add

s

3154

A solution of 245 mg of dimethyl sulfate in 10 ml of dimethylformamide is added and the mixture is stirred at room temperature for 1 hour. The reaction mixture is poured onto water and extracted with ethyl acetate. The extract is washed with water, dried and evaporated to remove the solvent. The residue is recrystallized from a mixture of ethyl acetate and n-hexane. J 509 mg of (+) - cis-2- (4-methoxyphenyl) -3- -oxy-5- 2- (N, N-dimethylamine o) e-chloro-2,3-dihydro-1,5 is obtained -Benzothiazepin-4 (5H) -one. M.p. 122-124 ° C (decomposition) .J

(oL) +, in (C 0.85 methanol).

Examples 2-4. The corresponding starting materials are treated as described in example 1 to obtain the compounds shown in 2 of Table 1, where the physicochemical characteristics of the 1,5-benzothiazepine derivatives are also given.

Example 5. 210 mg (+) Cis-2 2 | - (4-hydroxyphenyl) -3-acetoxy-5- 2- (N-methylamino) ethyl-8-chloro-2, 3-dihydro-1 , 5-benzothiazepin-4 (5H) -one, 250 mg of potassium carbonate and 140 mg of dimethyl sulfate are dissolved in 5 ml of methanol, and the solution is stirred at room temperature overnight. Insoluble materials are filtered off and the filtrate is evaporated to remove the solvent. The residue is dissolved in ethyl acetate and

about

Purified by chromatography on white gel (solvent: benzene: ethyl acetate: 1), converted into maleate and crystallized from a mixture of ethanol and ether.

Obtain 212 mg of (+) - cis-2- (4-met-hydroxyphenyl) -3-acetoxy-5 | 2- (H, M-dimethylamino) ethyl-8-chloro-2, 3-dihydro-1,5-benzothiazepin-4 (5H) -one maleate.

The physicochemical properties of this product are identical to those of the product obtained in Example 3 "

PRI me R 6. A solution of 1.82 g of (+) (4-hydroxyphenyl) -3-acetoxy-5- 2- (dimethylamino) ethyl-8-chloro--2,3-dihydro-1, 5-benzothiazepin-4 (5H) -α-in 20 ml of tetrahydrofuran is added to a suspension of 168 mg of sodium hydride (60% dispersion in mineral oil) in 20 ml of tetrahydrofuran at 26-27 ° C. 5

A solution of 485 ml of methylmethanesulfonate in 3 ml of tetrahydrofuran is added to the mixture, and then added dropwise.

74

in it 40 ml of dimethylformamide, which leads to foaming of the solution. After stirring for 30 mn at room temperature, the reaction mixture was poured into ice water. The solution is extracted with ethyl acetate, the extract is washed with water, dried and the solvent is evaporated from it. The solution is purified by chromatography on a silica gel column (solvent: chloroform: methanol 50: 1) and obtained in the form of an oil 870 mg (+) - cis-2- (4-methoxyphenyl) 3-acetoxy-5-Ј2- (dimethylamino) ethyl-8-chloro-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one. The product is converted to maleate and recrystallized from a mixture of ethanol and ether to obtain 1.05 g of (+) - cis-2- (4-methoxyphenyl) - -3-acetoxy-5- 2- (dimethylamino) -8-chloro-2, 3-dihydro-1,5-benzothiazepine-4- (5H) -one maleate. M.p. 158-1 ° C.

Example. A solution of 1.05 g of diazomethane in 65 ml of methylene chloride is added to a solution of 220 mg of (+) - cis-2- (4-hydroxyphenyl) -3-acetoxy-5-Ј2- - (dimethylamino) etch-3-chloro -2, 3-dihydro-1, 5-benzothiazepin-4 (5H) -one in 10 ml of methanol, the mixture is stirred overnight at room temperature. A few drops of ethyl acetate are added to the reaction mixture, after which the mixture is condensed. The residue is converted into maleate and recrystallized from a mixture of ethanol and ether to give 214 mg of (+) - cis-2- (4-methoxy-phenyl) -3-acetoxy-5- 2- (dimethylamino) ethyl-8-chloro-2, 3-dihydro-1,5-benzothiazepin-4 (5H) -one of maleate. 75% yield. M.p. 158-160 ° C.

Try on A mixture of 2.2 g of (+) - -cis-2- (4-hydroxyphenyl) -3-acetoxy- (dimethylamino) ethyl1-8-chloro-2,3-β-dihydro-1,5-benzothiazepin-4 (5H) - it, 160 g of methanol, 1.03 g of dicyclohexyl diamide and 5 ml of dimethylformamide are stirred for two weeks at room temperature. Water was added to the reaction mixture, and the solution was extracted with ethyl acetate. The extract is washed with water, dried and the solvent is evaporated from it. The residue is purified by chromatography in a silica gel column (solvent: chloroform: methanol 50: 1). The obtained (+) - cis-2- (4-methoxyphenyl) -3-aiotoxy-5- 2- (dimethylamino) ethyl-8-chloro-2,3-dihydro-1,5-benzothiazepin-4 (5H ) - -one is converted to maleate and recrystal51

lized from ethanol / ether to give maleate 0.57 g of (+) - cis - -2- (4-methoxyphenyl) -3-acetoxy-5-2- (dimethylamino) etch-8-chloro-2,3- di-hydro-1,5-benzothiazepin-4 (5H) -one. T.pp. 158-1 ° C.

PRI me R 9. The study of therapeutic action.

In these comparative experiments, the therapeutic effect of each compound was defined as the hypotensive activity, the vasodilator effect on the brain vessels and the coronary vessels.

The methods and results of these comparative experiments are presented below.

The following compounds were used in the comparative experiments: Compound Chemical name (Proposing compounds

1 (+) - cis-2- (4-methoxyphenyl) -3-acetoxy-5- 2- (dimethylamino) -8-chloro-2,3-dihydro-1,5-benzothiazepin-4 (5H) - it hydrochloride

2 (±) -cis-2- (4-methoxyphenyl) -3-acetoxy-5- 2- (dimethylamino) ethyl-8-chloro-2,3-dihydro-1,5-benzothiazepin-4 ( 5H) -one hydrochloride

3 (+) - cis-2- (4-methoxyphenyl) -3-acetoxy-5- 2- (N-methyl-M-ethylamino) -ethyl-8-chloro-2,3-dihydro -1.5 -benzothiazepin-4 (5H) --on 1-tartrate

Known analogues

4 (+) - cis-2- (4-methoxyphenyl) -3-acetoxy-5- 2- (di-methylamio), 3- -dihydro-1,5-benzothiazepine-4 (5H) -one hydrochloride (this compound is known as diltiazem)

5 (+) - cis-2- (4-methoxyphenyl) -3-acetoxy-5- 2- (dimethylamino) ethyl-2,3-dihydro-1, 5-benzothiazepine-4 (5H) - he is hydrochloride

6 (+) - CIS-2- (4-methoxyphenyl) -3-acetoxy-5- - (dimethylamino) ethyl-7-chloro-2,3-dihydro-1,5-benzo876

thiazepin-4 (5H) -one hydrochloride

7 (+) - cis-2- (4-methoxyphenyl) -3-acetoxy-5-2- (di-methylamino) etigu-7-chloro--2,3-dihydro-1,5-benzothiazepin-4 ( 5H) -one hydrochloride

Experiment 1. Hypotensive activity.

The test compound, dissolved or suspended in water, was orally administered at a dose of 30 mg / kg to rats with spontaneous hypotension (CGC) who were fasting overnight. After administration of the compound in rats, systolic pressure was measured using a tail imam.

The hypotensive activity of the test compounds was defined as a decrease in blood pressure — U mm Hg, which was calculated by the formula

Blood pressure drop (L mmHg) Blood pressure,

measured immediately before

the introduction of the test compound

Blood pressure measured after injection of test compound.

The results are presented in Tables 2 and 3. Table 2 shows the hypotension activity of each test compound, which was determined 4 hours after the administration of the indicated test compounds, and the hypotensive activity of each test compound, determined through 1,2,4, 6 and 8 hours after administration of the test compounds.

Experiment 2. Hypotensive activity and acute toxicity.

Antihypertensive activity.

Experiments were carried out according to the method of experiment 1, except that the test compounds were administered in the mouth in doses of 10, 30 and 100 mg / kg, respectively. Hypotensive activity was expressed as ED, -i.e. as a dose that is necessary in order to lower the blood pressure by 45 mm Hg.

Acute toxicity.

The test compound was dissolved or suspended in water and orally administered to male mice (25-30 g body weight).

Table 4 shows the values of the hypoenzive activity (ED45), 50% of the treatment dose (LD50), and safety factor (CDD0 / EDC5) for each 5 of the test compounds.

Experiment 3. Expanding effect on brain vessels.

Male dogs weighing 10-20 kg were anesthetized with 10 sodium pentobarbital (30 mg / kg, intravenously). The blood flow in the vertebral artery was measured continuously with an electromagnetic flowmeter with active ventilation.

The test compound solution in an aqueous 5% glucose solution and injected into the vertebral artery. The broadening effect on the vessels of the head moeg of the test compound was expressed as the ratio of the activity of the indicated compound to the activity of papaverine, which was determined from the dose-response curves of these compounds.

The results are presented in table.5. 25

Experiment 4. Expanding effect on coronary vessels.

Male dogs weighing 15–24 kg were anaesthetized with sodium pentobarbital (30–35 mg / kg, intravenously). After 30 thoracotomy, the blood flow in the left coronary artery bypass was measured with an electromagnetic flowmeter. The test compound, dissolved in physiological saline, 35 was injected into the coronary artery at a dose of 3 or 10 μg / kg. As a positive control, diltiazem (compound 4) dissolved in saline solution was injected into the coronary artery of the same cobalt 40 how her blood flow returned to normal. The expanding effect on the coronary vessels of the test compound and diltiazem was expressed as an increase in the total 45 blood flow, which was determined by the following formula: Increase in the total blood flow: Peak of the response of the coronary blood flow (U ml / min) x Half-period (min).

Half period means a period of 50 times during which at least half of the peak value of the coronary blood flow is maintained.

Further, on the basis of the result obtained above 55, the coefficient of force of the test compound with respect to diltiazem (compound 4) is equal to the ratio: increased total blood flow,

caused by the administration of the test compound / increased total blood flow caused by the administration of diltiazem.

The results of the experiment are presented in table 6.

As can be seen from the data of Tables 2–4, the proposed compounds 1-3 showed a higher and more prolonged hypotensive activity as compared with compounds 4–6. For example, from Table 2 it can be seen that the proposed compounds 1-3 showed a decrease in blood pressure by 45.5-71.6 mm Hg, while the administration of compounds 4-6 caused a decrease in blood pressure by no more than 14.3 mm Hg This means that the hypotensive effect of the proposed compounds 1-3 is 3.2-11 times higher than the analogous effect of compounds 4-6.

It is also seen from the data of Table 4 that when comparing EL45 (i.e., the dose required to reduce the pressure by 45 mm Hg), the hypotensive activity (ED45) of compound 1 is at least 6.1 higher than the analogous activity of compounds 4 (diltiazem) and 6, the safety factor, i.e. the ratio of 50% of the lethal dose (LD50) to the antihypertensive activity (EDC.5) of compound 1 is more than 7.8 times higher than that of compound 4 (diltiazem) and 6, in addition, the expanding effect on the cerebral vessels of compound 1 J3 is 5 times higher than that of Compound 7, and the effect of coronary dilatation of Compound 1 is 2.3 times higher than that of Compounds 4 (diltiazem) and 6,

Thus, in comparison with compounds 4-7, the proposed compounds 1-3 are most suitable as antihypertensive drugs, while compounds 1 and 3 are more suitable as drugs that have an expanding effect on the cerebral vessels and / or coronary vessels. because of their stronger or more prolonged therapeutic effects, and also because of their greater safety with such use.

F o rm ula invention

Claims (5)

1. A method of producing 1,5-benzothiazepine derivatives of the general formula OCH-i J CH2CH2NC where R is hydrogen or acetyl; X is lower alkyl, or their salts, characterized in that the compound of the general formula  About CH7CH2N CH; Ho where Rf - has the indicated values, X? - hydrogen or lower alkyl, is alkylated with an alkylating agent selected from lower alkanol, lower alkyl sulfonate, lower alkyl quaternary ammonium. five 0 five lower alkyl sulfate, lower diaaeoalkane and lower alkyl halide, and the desired product is given in free form or as a salt. 2. The method according to claim 1, -o tl and h a rail, and so that the alkylation is carried out by treatment with a lower alkanol at 0-40 ° C in the presence of a dehydrating agent. 3. Method 1, characterized in that the alkylation is carried out by treatment with a lower alkyl sulfate, lower alkyl sulfonate or lower alkyl halide at a temperature from 0 ° to reflux temperature in the presence of a base in an inert solvent. 4. Method of claim 1, characterized in that the alkylation is carried out by treatment with lower alkyl quaternary ammonium at a temperature of from 10 ° C to reflux temperature. 5. Method as claimed in claim 1, characterized in that the alkylation is carried out by treating with a lower diazoalkane at 0-40 ° C, preferably at 20-30 ° C, in an inert solvent. (-) - cis-2- (4-Methoxyphenyl) -3-hydroxy-5-Ј2- (M, M-dimethylaminsZ) ethyl-8-chloro-2,3-di-hydro-1,5-benzothiazepine - -4- (5H) -one (+) - cis-2- (4-methoxyphenyl) -ZH-acetoxy-5- 2- (M, M-di-methylamino) ethyl-8-chloro-2,3-β-dihydro-1,5-benzothiazepine - -4 (5H) -one (-) - cis-2- (4-11etoxyphenyl) -ZH-acetoxy-5- 2-chdimethyl-amino) ethyl-8-chloro-2,3-di-hydro-1,5-benzothiazepine-4 ( 5H) -OH 121-123 ° C (decomposition) MD - 142.7 (C 1.04, methanol) Maleate (recrystallized from ethanol - diethyl ether). Mp 158-160 ° C (° + 75.4 ° (, 0, methanol) hydrochloride. Mp. 128-132 ° C (decomposition) () D - 93.3 ° (, 872, ethanol) Number of rats Blood pressure mm Hg, determined after time h after dosing ABOUT Offerable 1 2 3 4 5 1 2 3 4 5 b 1 2 3 4 5 6 Famous 1 2 3 4 5 1 2 3 1 2 3 4 Compounds 202 210 202 201 209 175 186 208 199 212 197 220 232 209 224 232 203 analogues 205 209 203 215 209 197 203 215 210 204 214 211 Table Decrease in blood pressure, L mm Hg. (mean ± stat. error : i 71, 3 61.8 + 13.0 45.5 ± 2.9 12,241.6 6, 7i6.9 14.3Ј3.9  The number of rats in the experiment Compound 1 (proposed) 3 (proposed) 7 (known) Papaverine (Positive Control) Numerical values in parentheses — increase in total blood flow caused by the administration of diltiazem (compound 4) Table 5 Brain dilating action (force ratio) 25 10.4 5 one Table 6